Psychosocial stress, interpersonal sensitivity, and social withdrawal in clinical high risk for psychosis: a systematic review

Stress has repeatedly been implicated in the onset and exacerbation of positive symptoms of psychosis. Increasing interest is growing for the role of psychosocial stress in the development of psychosis symptoms in individuals at Clinical High Risk (CHR) for psychosis. A systematic review was therefore conducted to summarize the existing evidence base regarding psychosocial stress, interpersonal sensitivity, and social withdrawal in individuals at CHR for psychosis. An electronic search of Ovid (PsychINFO, EMBASE, MEDLINE, and GLOBAL HEALTH) was conducted until February 2022. Studies that examined psychosocial stress in CHR were included. Twenty-nine studies were eligible for inclusion. Psychosocial stress, interpersonal sensitivity, and social withdrawal were higher in CHR individuals compared to healthy controls and there was some evidence of their association with positive symptoms of psychosis. Two types of psychosocial stressors were found to occur more frequently with CHR status, namely daily stressors, and early and recent trauma, while significant life events did not appear to be significant. Greater exposure to psychosocial stress, emotional abuse, and perceived discrimination significantly increased risk of transition to psychosis in CHR. No studies examined the role of interpersonal sensitivity on transition to psychosis in CHR. This systematic review provides evidence for the association of trauma, daily stressors, social withdrawal, and interpersonal sensitivity with CHR status. Further studies investigating the impact of psychosocial stress on psychosis symptom expression in individuals at CHR and its effects on transition to psychosis are therefore warranted.


INTRODUCTION
Clinical High Risk for Psychosis (CHR), also known as prodromal, At-Risk Mental State (ARMS), and Ultra High Risk (UHR), denotes an elevated risk of developing psychosis 1 . CHR individuals are assessed using the Comprehensive Assessment of At-Risk Mental States (CAARMS) assessment tool 2 to determine one of three syndromes: attenuated positive symptoms (APS) (sub-threshold psychotic symptoms), brief limited intermittent psychotic symptoms (BLIPS) (brief psychosis lasting less than one week), or genetic risk and/or deterioration (GRD) (Positive family history of psychosis plus a decline in functioning) 2 . The CHR concept was devised in order to identify at-risk individuals thereby affording the opportunity for preventative strategies 3 .
Psychosis has been deemed to be a multifactorial polygenic disorder with heritability estimates ranging between 31% and 44% [4][5][6] . While this finding suggests that the etiology of psychosis involves a significant genetic contribution, environmental insults are also thought to play a critical role. Adverse life events have repeatedly been implicated in the development of First Episode Psychosis (FEP) 7 with 89% of FEP patients reporting one or more adversities compared to 37% of controls 8 . Specifically, childhood/ adolescent sexual, physical, and emotional abuse, physical/ emotional neglect, separation, and institutionalization were 4-17 times higher for the FEP group. Moreover, for each additional adversity, the risk of psychosis increased 2.5 times 8 . Similarly, CHR individuals were found to have experienced significantly more severe adverse events than controls, regardless of trauma subtype 9 . Specifically, CHR individuals were 5.5, 2.5, and 3.1 times as likely to report emotional abuse, physical abuse, and bullying victimization, respectively 9 . Yet, it is clear that not everyone who develops psychosis has experienced severe adversity, such as abuse, neglect, or separation, and that other environmental factors may also play a significant role. Specifically, psychosocial stress is emerging as a possible contributory factor in the onset of psychotic-like experiences in CHR individuals 10 . Psychosocial stress has been defined as any social or cultural situation that causes physical, emotional, or psychological strain on an individual 11 . The physiological effects of psychosocial stress include increased heart rate and variability, skin conductance, decreased brain volumes, inflammation, alteration in hypothalamic-pituitary adrenal axis function, and increased cortisol secretion 12 . Psychological consequences of psychosocial stress include reduced self-esteem and motivation, increased negative affect, aggression, and withdrawal from social situations 12 . These negative effects can increase the risk of psychopathology, which is consistent with the Stress-Vulnerability Model 13 . This model posits that an individual's predisposing bio-psychosocial vulnerability (biological, psychological, and social risk factors) interacts with stress caused by various life experiences leading to the manifest illness such as depression, anxiety, as well as psychosis 13 . Therefore, an individual with a high bio-psychosocial vulnerability will only need to experience a low level of (internal or external) stress in order to develop psychosis; while in contrast, an individual with a low overall level of bio-psychosocial vulnerability will need to experience a high level of stress in order to manifest the illness. Behavioral Sensitization has been proposed as a possible mechanism to account for the relationship between stress and psychosis symptoms 14 . This notion suggests that cumulative exposures to environmental insults produces an increased sensitivity to stress and elevated emotional responses to similar stressors subsequently experienced 14 . Indeed, early experiences of trauma and life events have been found to contribute to increased stress sensitivity in adulthood [15][16][17] and patients with psychosis have been found to react with more intense emotions to perceived stress in daily life compared to controls 18,19 , giving credence to the behavioral sensitization concept. Therefore, the stressvulnerability model denotes the effects of cumulative stress on a pre-existing trait vulnerability, while the concept of stress sensitivity refers to the magnitude of affective arousal in response to repeated stressors.
Exposure to psychosocial stress has been found to be higher in the CHR individuals compared to the general population 20 . Contrarily, another study found that the exposure to psychosocial stress may actually be comparable between these groups but was found to have a greater negative impact in the CHR group 21 . Indeed, a greater perception of psychosocial stress was associated with more severe positive symptoms in a CHR group compared to help-seeking controls 22 . Greater subjective distress in response to psychosocial stressors in CHR individuals may in part be accounted for by individual constitutional characteristics such as personality and temperament 22 , in addition to their level of sensitization, whereby repeated exposure to stress leads to an elevated affective response to subsequent stressors 14,23 . It is important to note that most measures of stress do not differentiate general stressors from psychosocial stressors perhaps because most, if not all, stressful events would contain a social component, highlighting the difficulty in ascertaining the differences between these two types of stressors. However, it is possible that they may exert similar effects on the stress response system if they are both appraised as challenging, threatening, or harmful 24 . It has therefore been suggested that the appraisal of an event as stressful, rather than the type of event, may be important in understanding the relationship between stress and the onset of psychosis 25 .
In regards to possible constitutional factors, interpersonal sensitivity refers to the undue and excessive awareness of, and sensitivity to, the behavior and feelings of others. This concept comprises of interpersonal awareness, a fragile inner self, need for approval, separation anxiety, and timidity 26 . High levels of interpersonal sensitivity have been characterized by avoidant behaviors such as social withdrawal and appeasement behaviors so as to avoid conflict or rejection by complying with the expectations of others 27 . The aforementioned coping strategies employed by individuals with high interpersonal sensitivity inadvertently affects social performance and functioning 28 .
Alongside personality traits, behaviors such as social withdrawal have also been investigated in psychosis. Social withdrawal can be defined as retreat from interpersonal relationships usually accompanied by an attitude of indifference and detachment 29 . Social withdrawal often leads to social isolation, loneliness, disturbed sleep hygiene, loss of support, and the development of psychiatric conditions 30 . Substance misuse, mood disorders, and psychotic disorders are one of many psychopathologies that can be associated with avoidant behaviors such as social withdrawal. In relation to psychosis, some have suggested that it precedes its onset 31 , while others argue it is a consequence of the disorder 32 . Compared to controls, CHR individuals exhibit greater levels of social withdrawal 33 , which is associated with increased symptomatology, such as positive and negative symptoms, reduced psychosocial and occupational functioning, and increased suicidal thoughts and substance misuse 30 . These behaviors in turn may contribute to the formation and persistence of psychosis symptomatology. Indeed, higher levels of social withdrawal have been associated with an increased likelihood of transition to psychosis 34 .
Psychosis symptomatology therefore appears to be influenced by a plethora of social factors such as psychosocial stress, interpersonal sensitivity, and social withdrawal. The aforementioned social factors have been observed to influence the development of symptoms and the progression of the illness, as well as impacting on long-term outcomes. Nevertheless, the reliability of these associations within the literature remains unclear. Furthermore, it remains unclear whether social factors are precipitating factors, perpetuating factors, or both. Therefore, a synthesis of the existing literature may help to elucidate the influence of psychosocial stress in individuals at CHR and its role in the transition to psychosis. To date, no systematic review has been conducted on the impact of different types of psychosocial stressors in CHR individuals incorporating the role of social behaviors and personality characteristics.
Therefore, the aim of this review was to summarize the existing evidence regarding the relationship between psychosocial stress, interpersonal sensitivity, and social withdrawal on transition to psychosis in CHR individuals. The following outcomes will be considered in the included papers: CHR status vs. controls, psychosis/affective symptomatology, and rate of transition to psychotic disorders.

METHOD Protocol and registration
This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines 35 . Methods and inclusion criteria were specified in advance and documented in a protocol registered with the International Prospective Register of Systematic Reviews (PROSPERO; PROSPERO registration: CRD42021264478).

Search strategy and selection criteria
A systematic search of Ovid (PsychINFO, EMBASE, MEDLINE, and GLOBAL HEALTH) was conducted, including studies from database conception to February 28, 2022. The following search strings were used: (at-risk mental state OR ultra-high risk OR clinical high risk OR attenuated psycho* OR prodrom* OR transition or conver* or psycho*) AND (interpersonal sensitiv* OR interpersonal awareness OR relational sensitiv* OR social withdrawal OR social avoidance OR social network OR social stress* OR social advers* OR psychosocial stress*).
Any length of follow-up and any date of publication were included. Eligible studies measured psychosocial stress, interpersonal sensitivity, or social withdrawal and CHR status. Studies written in languages other than English and conference abstracts were excluded from the review. The study selection process is summarized in the PRISMA flow diagram (see Fig. 1).

Data extraction process
A data extraction form was developed in Microsoft Excel. One review author (PR) extracted the following data from the included studies: (1) participant characteristics (CHR status) and the included paper's inclusion and exclusion criteria; (2) outcome measures (psychosocial stress, interpersonal sensitivity, social withdrawal); (3) additional outcomes (including symptom severity, transition to psychosis, early/recent trauma); (4) statistical analysis used; (5) risk of bias assessment outcome; and (6) main findings (including means, standard deviations, effect sizes, and confidence intervals, where available). Study screening was performed independently by one reviewer and was subsequently crosschecked by a second reviewer (KM). Disagreements were resolved by consensus. All study designs were included in the review, except case studies.
The Grading of Recommendations Assessment, Development and Evaluation working group methodology 36 was employed to assess the quality of evidence by examining the following domains: risk of bias, consistency, directness, precision, and publication bias. The quality of evidence was therefore rated as high, moderate, low, or very low. The risk of bias and certainty assessment was also performed.

Analysis
Due to the expected low power and sparsity of literature, a descriptive summary of findings was planned. Summaries of each study were written in a Microsoft Word document, which, combined with the data extraction form and the Grading of Recommendations Assessment, were used to draw out analytical themes. No additional analyses were conducted.

RESULTS
A total of 5222 articles were retrieved during the initial search and 4684 articles remained following de-duplication. Through the initial screening involving title and abstract review 4518 articles were removed, thus 166 full-text evaluations took place. The fulltext evaluations resulted in 29 articles matching the inclusion criteria for this review. Articles were excluded if they did not examine CHR status and at least one of the following variables: psychosocial stress, interpersonal sensitivity, or social withdrawal. Studies were also excluded if no full-text was available, if it was classified as a conference abstract, was not written in English, and if the study examined virtually constructed social situations rather than real-life occurrences.

Study characteristics
This review included 29 studies published from 1999 to 2021, with most of the studies published from 2011 onwards. Out of 29 studies, 25 of them were carried out in Western countries (USA, Canada, UK, Netherlands, Italy, and Australia), while only 4 studies were carried out in non-Western countries (China, Seoul, and Brazil). The total sample size of included studies was n = 3143. The sample size ranged from n = 25-764, with the average sample size consisting of 108 participants. The participants were mainly recruited through Universities or specialized clinics and GP referrals, while all the assessors possessed a relevant postgraduate or doctoral degree. Out of all the included studies, 16 were crosssectional in design, whereas 13 were longitudinal (1 to 5-year follow-up). In addition, one study employed a combined crosssectional and longitudinal design.

Population characteristics
Participants' age ranged from 16 to 29 (average = 20). In terms of gender, males comprised more than 50% of the sample in all of the studies. The measurement of socio-economic status was not reported in 6 studies, while other studies measured educational achievement, employment status, or social class. The average years spent in education for CHR subjects was~13.69, which was reported in 4 studies, while 6 studies looked at education level through the highest level of attainment. Three studies reported that the highest level of education was high school, while 3 studies reported it as university completion. Eight studies examined employment status of the clinical sample with 4 studies reporting higher rates of unemployment amongst CHR population and 4 studies reporting the opposite. The ethnicity of study participants was only reported in 13 studies. The samples were predominantly Caucasian, ranging from 50-80% of the sample. The exception was two studies 37,38 , which included a higher proportion of ethnic minority participants. Lastly, control groups were demographically matched to the clinical sample.

Clinical and psychosocial stress measures
The following measures were employed to determine CHR status and transition to psychosis: Structured Interview for Prodromal Symptoms (SIPS) 39 46 .
Furthermore, the frequency and severity of psychosocial stress was measured using the following outcome measures: Childhood Trauma and Abuse scale 47 ; Behavior Assessment for Children-Second Edition (BACS-2) 48  Lastly, the concepts of social withdrawal and interpersonal sensitivity were measured using the following scales: Premorbid Adjustment Scale 59 ; Social Interaction Scale 60 ; Social Functioning Scale 61 ; and the Interpersonal Sensitivity Measure 26 .

Risk of bias and certainty assessment
The risk of bias assessment is summarized in Table 1 for crosssectional studies and Table 2 for longitudinal studies. The certainty assessment was conducted using the GRADE criteria and deemed the effects and conclusions of this systematic review as moderate. The moderate score was given due to the high consistency, precision, and directness found in the included studies. The potential for risk of bias was due to lack of blinding and the  possible effects of confounding variables, which prohibited granting a higher-ranking score.
Effects of psychosocial stress, social withdrawal, and interpersonal sensitivity on psychosis risk From the included studies, 16,8, and 5 studies examined the effect of psychosocial stress, social withdrawal, and interpersonal sensitivity on risk of psychosis in individuals at CHR, respectively (see Tables 3-8).
Psychosocial stress and psychosis risk From the total of 16 studies, 13 studies reported higher levels of psychosocial stress in the CHR group compared to controls, while 3 studies found no difference between these groups (see Tables 3  and 6). The significant association was mainly driven by the presence of trauma (10 out of 13 studies), while the nonsignificant associations defined psychosocial stress as significant life events (2 studies) or as daily hassles (1 study).
All ten studies examining trauma noted significantly higher levels in CHR individuals compared to controls. Similarly, the two studies examining general psychosocial stress also demonstrated significant associations with CHR individuals compared to controls. However, the two studies investigating significant life events found no difference between CHR and control groups.
Nine studies measured the association between the psychosocial stress and symptom severity. Five studies found increased symptomatology (positive and/or negative) in CHR individuals who experienced greater rather than lower levels of psychosocial stress, and 4 studies found no relationship between psychosocial stress and symptom severity. Seven studies examined risk of transition, and 3 studies found an association between elevated psychosocial stress and increased risk of transition to psychosis 21,62,63 . Greater exposure to life events and distress associated with these events were found in CHR individuals who transitioned to psychosis compared to those that did not 21 , while emotional abuse increased the risk of transition to psychosis 3.8 fold in CHR individuals 63 . Perceived discrimination also increased risk of transition in CHR individuals by 52.4% for every unit increase in scores on lifetime perceived discrimination 62 .

Social withdrawal and psychosis risk
Eight studies examined social withdrawal in CHR individuals (see Tables 4 and 7). All but one study 64 reported higher levels of social withdrawal in individuals at CHR as compared to controls. One of the studies examined social withdrawal prior to CHR identification 65 while the others measured its presence in individuals deemed to meet CHR criteria. Four studies examined the association between social withdrawal and psychosis symptomatology, two of which found a positive correlation, while the other two found no association between the levels of social withdrawal and the worsening of psychosis symptoms in CHR individuals. Two studies found higher levels of social withdrawal and subsequent conversion to psychosis.

Interpersonal sensitivity and psychosis risk
Five studies examined interpersonal sensitivity in CHR individuals (see Tables 5 and 8). All five studies found significantly higher levels of interpersonal sensitivity in CHR individuals compared to controls. Only two studies examined interpersonal sensitivity in relation to psychosis symptomatology and a positive correlation was found for both positive and negative symptoms. Lastly, no study included in this review measured the effect of interpersonal sensitivity on transition risk.   = 0.01).
These findings suggest that a positive parent-child relationship may be a protective factor against social stress for those at risk for psychosis. Findings provide additional evidence to suggest that interventions that simultaneously target both social stress and parent-child relationships might be relevant for adolescents and young adults at clinical high risk for psychosis. No significant correlations emerged between the CTQ total score and baseline levels of APS severity, distress associated with APS and functional outcomes. However, there was a significant positive correlation (r = 0.23, P = 0.044) between the CTQ total score and the CAARMS suicidality and self-harm baseline score.
The high prevalence of Childhood Trauma (CT) in CHR individuals and its association with suicidality and self-harm underlines the importance of inquiring about CT during clinical assessments.
A. Georgiades et al. No significant association was found between childhood adversity subscales and the severity of positive symptoms at baseline and at 4-year follow-up. No significant association was found between total childhood adversity scores and any of the childhood adversity subscales (emotional abuse, physical abuse, sexual abuse, emotional and physical neglect) and transition to psychosis at 4-year follow-up.
A. Georgiades et al. (MSPSS) CHR reported significantly higher stress levels compared to FEP patients. Both patient groups showed lower self-esteem compared to controls, and the CHR group reported lower social support and active coping than controls.
In the CHR group, higher stress levels and lower self-esteem were associated with more severe positive and depressive symptoms on the Brief Psychiatric Rating Scale. Multiple regression analyses revealed that stress was the only significant predictor for both symptom measures and that the relationship was not moderated by self-esteem. These findings show that CHR individuals experience high levels of psychosocial stress and marked deficits in protective factors. The results suggest that psychosocial interventions targeted at reducing stress levels and improving resilience in this population may be beneficial in improving outcomes.
A. Georgiades et al. CHR individuals rated events as more stressful, and those who progressed to psychosis reported a greater frequency of LE and greater stress from events compared to those whose prodromal symptoms remitted.
There was also some evidence of stress-sensitization; those who experienced more stress from LE rated current Daily Hassles (DH) as more stressful. The results indicate that the "prodromal" phase is a period of heightened stress and stress sensitivity, and elevated cumulative lifetime exposure to stressful events may increase reactions to current stressors.

Vargas et
al. 126 Cross  Brief Social Phobia Scale (BSPS) CHR and FEP group's SOFAS scores did not significantly differ from each other, but both groups were rated as functioning at a significantly lower level than HCs.
HCs performed significantly better on interpersonal communication than the CHR group, as they were communicating more frequently with others.
On the WHODAS, the CHR and FEP groups reported experiencing significantly more difficulty on the following subscales: understanding and communication, self-care, getting along with people, life activities, and participation in society, compared with HCs. The CHR and FEP groups did not differ from each other on any of these subscales. For the CHR group, increased levels of depressive symptoms were associated with decreased levels of both quantitative and qualitative measures of social functioning (i.e., withdrawal/social engagement, interpersonal communication and getting along with people). Significant correlations were found only between positive symptoms and the qualitative measures of disability; three of these four associations were for the CHR group only. Specifically, those at risk who reported more positive symptoms also indicated more difficulty with self-care (r There were no significant correlations observed between positive symptoms and any of quantitative social functioning (SFS) scores for CHR or FEP group. Rating Scales for Depression & Anxiety (HRSD)/ HRSA) Global Assessment of Functioning (GAF) 37 individuals (50%) made a transition to psychosis at 12month follow-up The most reliable scale-based predictor was the degree of presence of schizotypal personality characteristics. Individual items assessing odd beliefs/magical thinking, marked impairment in role functioning, blunted or inappropriate affect, anhedonia/asociality and auditory hallucinations were also highly predictive of transition, yielding good sensitivity (84%) and specificity (86%) and odds ratio of 6.2. These predictors are consistent with a picture of poor premorbid functioning that further declines in the period up to transition.

Bio-psychosocial model of transition to psychosis
The biological and neurodevelopmental vulnerabilities that play a key role in the stress-vulnerability model include hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis, dysregulation of neurotransmitters such as dopamine, GABA, and glutamate, aberrant salience, increased stress sensitivity and emotional reactivity to stressors, epigenetic effects (modification to the genome that affect gene expression without altering the DNA sequence), and gene-environment interactions (genetic factors influence the impact of an environmental exposure on an individual) [66][67][68] . Psychological factors include core beliefs and appraisals, emotions, attachment style, social cognition (set of neurocognitive processes related to understanding, recognizing, processing, and appropriately using social stimuli in one's environment), and theory of mind deficits (the capacity to infer one's own and other persons' mental states) [69][70][71][72][73] ; while social factors include the experience of trauma (physical, sexual, and emotional abuse, physical and emotional neglect, and parental loss), life events, and daily hassles [74][75][76] .
Based on the findings of the present paper, we propose the following Bio-psychosocial Model of Transition to Psychosis (see Fig. 2). This is a conceptual framework for integrating the influence of biological, psychological, and social factors in the transition to psychosis. Bio-psychosocial vulnerabilities, coupled with trauma/significant life events, lead to the formation of core beliefs, which are re-activated in response to psychosocial stressors. This core belief reactivation, in addition to the influence of interpersonal sensitivity, appraisals of stress, and social withdrawal, may give rise to increased affective arousal, which may be further amplified by the influence of cognitive biases and maladaptive coping. This affective pathway contributes to the generation of anomalous experiences/sub-threshold psychosis symptoms and the subsequent search for meaning for these unusual experiences, which may then lead to the formation of manifest psychosis. This model suggests that an underlying biopsychosocial vulnerability coupled with exposure to trauma/ significant life events during one's early life leads to the formation of core beliefs about oneself, others, and the world (e.g., I'm worthless, others are untrustworthy, world is dangerous) 71 . Indeed, compared to healthy controls, CHR individuals reported significantly more negative beliefs about self and others and significantly less positive beliefs about self and others 77 . Moreover, negative core beliefs have been found to partially mediate the relationship between childhood trauma and persecutory beliefs and have been shown to be characteristic of patients with psychosis [78][79][80][81] . These authors concluded that these findings provide preliminary evidence about the cognitive mechanisms that may underlie the association between childhood trauma and later risk for psychosis.
Early experiences shape our attachment style and can lead to an interpersonally sensitive style of relating, which would make the individual hypervigilant to threat and hypersensitive to ambiguity and perceived rejection/harm from others 71,82,83 . Social withdrawal would remove opportunities to receive positive reinforcement/gathering corrective information, which would in turn foster ruminative/erroneous thinking, which would negatively impact one's mood 84 . Psychosocial stress (trauma/significant life events/ daily hassles) would drive subsequent appraisals of such events, such as "I am a failure/inferior/unlovable/vulnerable/weak" inducing dysregulation of the HPA axis and the dopaminergic system. Appraisals of stress may also influence social withdrawal and interpersonal sensitivity, which both may in turn further reinforce the appraisal of stress. For example, an interpersonal sensitive style of relating may misinterpret the actions of others as threatening/rejecting while ensuing social avoidance would preclude the receipt of disconfirmatory evidence, thereby maintaining the appraisal of stress. Social context and frequency. Participants reported whether they were alone (i.e., "lone" and "alone with pet") or they reported with whom they were (i.e., "classmates", "friends", "family", "stranger"). The   The higher the interpersonal awareness (rs=0.52, P = 0.001), separation anxiety (rs=0.71, P < 0.001), fragile inner self (rs=0.51, P < 0.001) and total IPSM (rs=0.52, P < 0.001) scores among CHR participants, the higher the level of paranoid ideas and suspiciousness.
Higher sensitivity to interpersonal interactions, anxiety about separation from significant others and sense of having an inner or core self that is unlikeable and needs to be hidden from others were all associated with higher numbers of positive prodromal symptoms. Among participants with an CHR, total IPSM score (rs=0. 40 Role (GF: RS) CHR individuals showed higher IPSM scores and lower GF: SS and GF:RS scores than HCs. A statistically significant negative correlation between two IPSM subscales (Interpersonal Awareness and Timidity) and GF: SS was found in both groups. Statistically significant correlations were found between interpersonal sensitivity and negative prodromal symptoms in both groups. In CHR individuals, the higher the sensitivity to interpersonal interactions (rs =0.292, P = 0.002), the anxiety about separation from significant others (rs =0.480, P = 0.002) and the sense of having an inner or core self that is unlikeable and needs to be hidden from others (rs =0.320, P = 0.047), the higher the level of negative prodromal symptoms. Interpersonal awareness and Timidity aspects of interpersonal sensitivity were associated with low levels of social functioning. Assessing and treating interpersonal sensitivity may be a promising therapeutic target to improve social functioning in CHR individuals.
In addition, if the psychosocial stress experienced later in life is thematically similar to the trauma/significant life events during one's early life, it may serve to reactivate pre-existing core beliefs, further inducing a HPA stress response, elevated affective reactivity, and heightened stress sensitivity. Increased affective arousal/emotional dysregulation, in addition to the influence of cognitive biases, and maladaptive coping (e.g., rumination, substance misuse, emotionoriented coping) may subsequently contribute to the formation of anomalous experiences as typified in the CHR state. One's attempt to make sense of their experiences, otherwise known as their search for meaning, may then lead to the formation of manifest psychosis, such as delusions and hallucinations 85 . The search for meaning refers to the search for an explanation for anomalous experiences, recent events, or arousal and in doing so; pre-existing beliefs about self, world, and others are drawn upon 85 . These positive symptoms of psychosis in turn may reflect exaggerated themes of pre-existing insecurities and/ or interpersonal concerns (e.g., repeated historical experiences of childhood physical abuse is likely to lead to the development of a vulnerability core belief, which would be reactivated by a critical incident concerning physical threat from others such as a mugging). This may give rise to persecutory delusions of threat of harm from others and congruent auditory hallucinations (e.g., voice saying "you're in danger", "don't go outside"). Therefore, comprehensive assessments exploring the client's early life experiences/significant life events, core beliefs, psychosocial stressors and associated theme (e.g., intrusion, harm, loss of control, helplessness, unlovability, worthlessness, weakness, inferiority), appraisals of stress, interpersonal sensitivity, social withdrawal, cognitive biases, maladaptive coping, affective responses, and emerging anomalous experiences/psychosis presentation (delusional and/or hallucinatory subtype) would aid in the development of personalised formulations and targeted interventions.

DISCUSSION
This systematic review sought to synthesize the literature examining the relationship between psychosocial stress and onset of psychosis in CHR individuals. Psychosocial stress, interpersonal sensitivity, and social withdrawal were higher in CHR individuals compared to healthy controls and there was some evidence of their association with positive symptoms of psychosis. There was also some evidence to support the role of psychosocial stress and social withdrawal in the transition to psychosis and no studies to date have examined the role of interpersonal sensitivity on transition to psychosis in CHR, which proposes avenues for future research.
While the present review focuses on the existing evidence of the relationship between psychosocial stress and risk of psychosis in individuals at Clinical High Risk (CHR) for psychosis, our companion review (Almuqrin et al. submitted) considers such evidence in individuals with a First Episode of Psychosis (FEP).

Psychosocial stress
A repeated finding of the present review was for the association between higher levels of psychosocial stress in CHR individuals compared to controls. It is important to note that most studies driving this association examined trauma rather than significant life events or daily hassles, each of which are conceptually distinct constructs that need to be differentially defined and studied in relation to CHR symptomatology and conversion to psychosis. Psychosocial stress has been associated with increased positive and negative symptoms in individuals at CHR and appears to occur in a dose-response manner, as the greater the level of psychosocial stress experienced, the greater its impact on symptom severity 22 . This is in line with the dysregulation of the HPA Axis and the stress-vulnerability model regarding psychosis symptomatology arising from the cumulative effects of stress on a pre-existing bio-psychosocial vulnerability 13 . Interestingly, a labbased study examining the effects of an experimentally induced psychosocial stressor found that CHR individuals produced higher overall cortisol levels from the pre-anticipation period through to the recovery period of the Trier Social Stress Test and exhibited higher levels of subjective stress prior to the stressor compared to controls 86 . These findings provide further support for the stressvulnerability model and highlight the importance of examining the biological and subjective impact of psychosocial stress in CHR to further elucidate possible mechanisms of transition to psychosis. Environmental risks have also been found to act additively and synergistically with childhood trauma [87][88][89] and stressful life events 90,91 , contributing to the persistence of subthreshold psychosis symptoms in the general population. Psychosocial stressors such as childhood trauma and stressful life events have further been associated with higher levels of positive, negative, and depressive symptoms in the general population 92,93 .
In addition, these psychosocial stressors, along with polygenic risk  134 Yes n/a n/a Mushtaq et al. 124 Yes n/a n/a   117 Yes n/a n/a Chudleigh et al. 104 Yes No n/a Dragt et al. 65 Yes Yes Yes Hogdes et al. 118 Yes n/a n/a Jang et al. 131 Yes n/a n/a scores were found to exhibit independent additive effects on these three dimensions of subclinical psychosis 92,93 further supporting the stress-vulnerability hypothesis. However, it is important to note that no gene-environment interaction was found 93 . These general population studies appear to parallel the CHR findings 22 and are consistent with the stress-vulnerability and stress sensitivity models, whereby the cumulative effects of stress increase the likelihood of psychosis expression and increased affective arousal in response to such stressors, respectively. However, the finding of a positive correlation between psychosocial stress and positive psychosis symptoms in both CHR and non-CHR help-seeking controls 22 suggests that the effects of psychosocial stress on psychosis symptomatology appears to be independent of clinical vulnerability to psychosis, thereby only providing partial support for the stress-vulnerability model. A bidirectional relationship may also occur in that psychosis symptomatology may also elicit unwanted interpersonal responses leading to further experiences of psychosocial stress 22 . It has also been found that compared to healthy controls, individuals at CHR are significantly more distressed by stressful events and that the appraisal of these events differentiated CHR individuals from controls 21,25 . However, it is important to note that to date, the majority of case-control studies examining CHR have utilized healthy non-clinical controls, as opposed to help-seeking (i.e., psychiatric) controls, which risks attributing group differences to psychosis-risk status rather than to non-specific psychopathology and comorbidities occurring in the CHR group 94 . The inclusion of both healthy controls and help-seeking samples in CHR would aid in elucidating a psychosis specific vulnerability, as opposed to a more general mental illness vulnerability 94 .
Psychosocial stress and psychosis onset Only three out of seven studies found a significant association between elevated psychosocial stress and increased risk of transition to psychosis 21,62,63 . Greater exposure to psychosocial stress, emotional abuse, and perceived discrimination were found to significantly increase the risk of transition to psychosis in CHR individuals compared to controls. It is important to note that the three studies that demonstrated significant associations with transition to psychosis had a 24-month follow-up period and sample sizes ranging from 259 to 764 CHR individuals and 162 to 280 controls, which contrasts the 35-105 CHR individuals and 24-28 controls in the non-significant studies and a shorter 12month follow-up period. Therefore, the lack of significant findings regarding psychosocial stress and transition to psychosis in CHR may be due to existing studies being statistically underpowered to detect such effects and not having a long enough follow-up period to capture cases of transition.

Interpersonal sensitivity
All five studies found significantly higher levels of interpersonal sensitivity in CHR individuals compared to controls. Higher levels of interpersonal sensitivity exhibited by CHR individuals compared to controls is congruent with the theory that certain personality characteristics may predispose individuals to mental illness, such as psychosis 95 . Indeed, interpersonal sensitivity has been associated with a greater severity of psychosis symptomatology. This finding implicates the important role of social interactions as a factor in influencing one's well-being. Moreover, this relationship may indeed be bi-directional as individuals interact with their environment, which in turn impacts on the individual 66 . High interpersonal sensitivity can give rise to rumination about social performance and speech, preoccupation with the emotions displayed, and excessive focus on other people's opinions, which may hinder social performance. Feelings of exclusion and perceptions concerning a lack of understanding from others can negatively impact on self-esteem, confidence, and motivation, which could exacerbate negative symptoms such as negative selfimage, asociality, and avolition 96 .
In respect to positive symptoms of psychosis, increased levels of distress and subsequent avoidance of social situations could possibly account for their association with interpersonal sensitivity. The increased levels of distress could be attributed to one's preoccupation with receiving negative social feedback and perceptions of a lack of approval from others. Preoccupation with social feedback would elicit both physiological and psychological reactions, thereby increasing levels of stress 97 . In regard to coping with stress, it has been found that CHR individuals reported feeling significantly more distressed by events, felt that they coped more poorly, and employed more emotion-oriented coping as opposed to task-focused coping 25 . These authors also found that compared to controls, CHR individuals were less likely to employ social diversion as a means of coping, which involves engaging with others to divert attention from stressors.
Even though the evidence from this review supports the concept of higher levels of interpersonal sensitivity leading to worsening symptomatology in CHR, it is useful to note that only two studies examined this association and further investigations are needed to examine the strength of this association.
No study to date has examined the relationship between interpersonal sensitivity and psychosis transition. The findings of increased severity of psychosis symptomatology in relation to interpersonal sensitivity might suggest the possibility of a direct link with conversion to psychosis. Nevertheless, it could also be possible that symptoms are affected by this personality trait but it may not extend to conversion to psychosis, as was the case for social withdrawal. Henceforth, without a number of studies investigating this aforementioned relationship, no conclusion can be drawn at this time.

Social withdrawal
Compared to controls, social withdrawal was frequently observed in CHR individuals, who might avoid social situations due to emerging suspiciousness 98 . Moreover, auditory and/or visual hallucinations may directly impact the individual's capacity to engage and follow a conversation, which may be distressing and may negatively impact self-esteem. Individuals may thus choose to avoid social situations to circumvent anticipated embarrassment and rejection from others 98 . Social avoidance/withdrawal may ensue failed attempts at social engagement or may be present pre-morbidly 99 . Unfavorable feedback from social interactions can also lead to social avoidance so as to avoid unpleasant feelings 100 . Social withdrawal results in a lack of social support, which in turn minimizes potential sources of external support that could challenge delusions and hallucinations, thus indirectly causing a greater reality mismatch 101 .
The mixed findings regarding the association between social withdrawal and increased symptomatology might be accounted for by the inclusion of varied outcome measures for social functioning. Interestingly, the two negative findings employed the Social Functioning Scale (SFS) 61 , which was validated on an outpatient schizophrenia sample with a mean illness duration of 8.8 years and assesses seven areas including social engagement/ withdrawal, interpersonal behavior, prosocial activities, recreation, independence-competence, independence-performance, and employment/occupation. Of the two studies that found a positive association between social withdrawal and symptoms, one employed the Premorbid Adjustment Scale (PAS) 59 , which measures the level of functioning in four major areas: social accessibility-isolation, peer relationships, ability to function outside the nuclear family, and capacity to form intimate socio-sexual ties. The PAS may therefore be more nuanced and applicable to the CHR population compared to the SFS, possibly accounting for the significant positive finding. The other significant finding employed the Experience Sampling Method (ESM) 102 , which captures daily life data regarding social context and frequency, as well as emotional reactivity throughout the day for seven consecutive days. This is advantageous to questionnaire measures, as it allows for the investigation of experiences and interactions within a real-world context 103 . The mixed findings regarding the association between social withdrawal and increased symptoms of psychosis might also be accounted for by the included studies tending to examine positive rather than negative symptoms, highlighting the presence of a possible publication bias. It has been suggested that social withdrawal is more closely related to the latter rather than the former. Indeed significant associations have been found for social withdrawal and negative symptoms in CHR individuals 104 . The closer association between social withdrawal and negative symptoms may be due to the similarities in its characteristics. Social withdrawal is presumed to result from the lack of motivation to engage in social interactions, asociality, which is one of the primary negative symptoms 105 . Henceforth, the results might have been different if the association between social withdrawal and negative symptoms was assessed in the included studies.
The perception of social support may benefit reality testing, as it can weaken the intensity of delusions and hallucinations, subsequently improving insight in CHR 101 . If delusions and hallucinations remain unchallenged, they may intensify and exacerbate distress. It has also been posited that the lack of sensory stimulation derived from social interactions may contribute to an increase in hallucinatory experiences owing to the over-compensatory mechanisms of the nervous system 106 . In addition, socially withdrawn CHR individuals may not recognize their emerging illness and need for treatment, which would adversely affect their recovery 107 .
Two studies found higher levels of social withdrawal and subsequent transition to psychosis. The higher transition rates in CHR individuals who exhibit higher levels of social withdrawal can possibly be explained by a social network approach. Having social support can greatly impact one's well-being in number of positive ways such as increasing self-esteem, improving confidence, providing an opportunity for new experiences, easing stress, and preventing loneliness. Alternatively, the lack of social networks can lead to social isolation, poor psychosocial functioning, and an increase in negative thoughts and feelings 108 . In addition, it has been suggested that higher transition rates are linked to a longer duration of untreated psychosis, as a result of a lack of social support. Having a close friend or supportive family environment can facilitate the more timely identification of behavioral change and mental health deterioration, which could then precipitate prompt engagement with services and the initiation of treatment 109 .

Strengths and limitations
This is the first review to synthesize the literature regarding psychosocial stress, social withdrawal, and interpersonal sensitivity in CHR and highlights the importance of social factors in CHR symptomatology and their possible involvement in conversion to psychosis. However, this review has some limitations. The majority of studies included in the present review had a higher number of male than female participants. Poorer premorbid and psychosocial functioning, and increased substance misuse has been found in males compared to females, which would negatively impact on their ability to form social connections and to seek help from others 110 . Substance misuse may also negatively impact symptom severity, functioning, engagement with services, and recovery 111,112 . The included sample was predominantly Caucasian, which limits the representativeness and generalizability of the sample to Black and Minority groups, which have a higher incidence of psychosis 113 . Alongside the characteristics of the sample, the size of it could also have an impact on the results. Even though the average sample size was 100, 9 out of 27 studies had sample sizes under 100 participants. Small sample sizes can affect the reliability and representativeness of results. Additionally, the majority of the studies included in this review originated from Western countries, while a small number of studies were conducted in developing countries. This therefore limits the generalizability of the present findings 114 .
Furthermore, the present review examined three different types of psychosocial stress (trauma, significant life events, and daily hassles), however some studies did not specify the social stressor but referred to it by the collective name of social/psychosocial stress. Using this umbrella term limits the possibility of examining which factors influence CHR status and transition outcomes.
Trauma, significant life events, and daily hassles represent conceptually distinct constructs that need to be differentially defined and studied in relation to CHR symptomatology and their role in transition. Therefore, specifying the type of stress would enhance the specificity of future investigations. In addition, it would be important to examine the effect of more recent and historical significant life events, as well as the appraisal of those events, as they may exert a differential influence on symptom formation and expression. Indeed, appraisals of stress have been found to differ between CHR individuals and controls and may impact on psychosis transition 25 .

Clinical implications and future directions
This review synthesized the literature examining psychosocial stress, social withdrawal, and interpersonal sensitivity in individuals at CHR for psychosis. The negative impact of psychosocial stress on CHR individuals in terms of psychosis symptomatology and transition to psychosis emphasizes the importance of social factors in the CHR state. The proposed Bio-Psychosocial Model of Transition to Psychosis offers an explanatory framework for devising personalized, idiosyncratic, and symptom-specific formulations accounting for psychosis emergence in CHR and FEP. It highlights the possible mediating role of core beliefs in explaining the relationship between trauma and psychosis symptomatology, which would benefit from further investigation of core beliefs in CHR, FEP, and controls and their association with hallucinatory and delusion subtypes (e.g. persecutory, grandiose, religious, somatic, bizarre). This would subsequently inform psychosocial treatments, allowing for targeted interventions. For example, psychosocial treatments, such as Cognitive Behavior Therapy for Psychosis (CBTp) could employ this Bio-Psychosocial Model of Transition to Psychosis within collaborative case formulations with clients and could draw upon social aspects of treatment, such as social skills training, encouraging help-seeking behaviors, utilizing social support, and enhancing communication skills. This would also help to avoid the negative impact of social withdrawal. Additionally, Group CBTp could be employed to target social isolation and withdrawal, while also enhancing social skills in a group setting. Current interventions advocated for CHR include CBTp for alleviating symptoms and preventing transition to psychosis, as well as Cognitive Behavioral Family Interventions for Psychosis (CBFIP) in order to reduce stress, improve problemsolving, and enhance interpersonal communication skills 115 . However, neither intervention explicitly targets the appraisal of psychosocial stress and associated coping, which could improve social functioning in CHR individuals. This therefore affords an opportunity to devise and develop targeted CBTp interventions with an explicit focus on minimizing the effects psychosocial stress and improving social functioning. Additionally, as psychosocial stress is often unavoidable, learning to identify and challenge unhelpful appraisals and maladaptive coping leading to increased distress may enhance well-being. To date, there has been a lack of emphasis on the appraisals of stressful events, therefore their exploration in CHR, FEP, and controls in future studies are warranted. Interpersonal sensitivity could also be a therapeutic target, with the aim of elucidating vicious cycles and enhancing more adaptive behavioral coping methods of social integration rather than social avoidance. Therefore, identifying potential cognitive and affective mediators accounting for the relationship between psychosocial stress and psychosis could hold significant implications for the identification, prevention, and treatment of CHR individuals.

DATA AVAILABILITY
Data sharing is not applicable to this article as no new data were created or analyzed in this study.